1. Field of the Invention
This invention relates to a new process for producing the immunosuppressant agent, L-683,742, utilizing the new mutant microorganism Streptomyces hygroscopicus subsp. ascomyceticus (MA 6646) ATCC No. 53855, being a blocked mutant of Streptomyces hygroscopicus subsp. ascomyceticus (MA 6475), ATCC No. 14891. The process involves culturing the new microorganism under aerobic fermentation conditions in an aqueous carbohydrate medium containing a nitrogen nutrient.
2. Brief Description of Disclosures in the Art
In 1983, the US FDA approved cyclosporin, an extremely effective anti-rejection drug that revolutionized the field of organ transplant surgery. The drug acts by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein.
As effective as the drug is in fighting transplantation rejection, it suffers drawbacks in causing kidney failure, liver damage and ulcers which in many cases can be very severe.
EPO Publication No. 0184162 to Fujisawa, hereby incorporated by reference, describes a new macrolide, immunosuppressant FK-506 which is reputed to be 100 times more potent than cyclosporin. The macrolide, as well as the structurally related FK-525, are produced by fermentation of a particular strain of Streptomyces tsukubaensis. Also described are the closely related macrolide immunosuppressants, FK-520 and FK-523, produced by S. hygroscopicus subsp. yakushimaensis.
U.S. Pat. No. 3,244,592 to T. Arai describes the culturing of Streptomyces hygroscopicus var. ascomyceticus to produce the antifungal "ascomycin".
U.S. Ser. No. 213,025 U.S. Ser. No. 213,025 (case Docket 17767) by S. T. Chen, E. S. Inamine, B. H. Arison, L. S. Wicker, (assigned to Merck & Co. Inc.) hereby incorporated by reference, discloses a new immunosuppressant agent, "demethimmunomycin", L-683,742, a C-31 demethylated analog of L-683,590 (FK-520) produced by culturing the microorganism Actinoplanacete sp. (MA 6559), ATCC No. 53771, in the presence of L-683,590 to effect a biotransformation of L-683,590.
There is, however, no description in the literature of the production of the immunosuppressive agent L-683,742 directly from the fermentation of a microorganism which does not require the presence of L-683,590 starting material.
New processes in this regard are constantly being searched for in the field.